Drug addiction is a neurological and psychological disorder characterized by compulsive intake, craving and seeking of drugs with negative impacts that adversely affect the lives of the drug abusers. Addiction has recently been proposed to be a pathological form of learning and memory, which requires long-term changes of neural circuits. Consistent with this proposal, our recent studies reveal that chronic treatment with opioids alters the stability of dendritic spines in cultured dissociated neurons. The ultimate goal of my scientific career is to significantly advance our integrated understanding of drug addiction at both system and cellular levels. The scientific objective of my research is to determine the cellular mechanism underlying opioid modulation of dendritic spines. My present research is funded by a National Institute on Drug Abuse (NIDA) R01 grant (DA020582) which contains three Specific Aims: (1) to further characterize the roles of MORs and their internalization in postsynaptic modulation of dendritic spines. (2) To identify and determine the Rho GTPase that mediates opioid modulation of dendritic spines. (3) To identify and determine the protein kinase(s) that mediate opioid modulation of dendritic spines. This K02 award will allow me to significantly reduce my teaching hours so that I can devote more of my effort to research (increased from 50% to 75% of total effort). I will use the extra 25% effort to strengthen and broaden the R01 project in two ways: (1) enhancing the Specific Aims 1 and 3 with newly proposed experiments using brain slices prepared from different regions of the brain including the striatum, ventral tegmental area (VTA), frontal neocortex and hippocampus: Our recent unexpected results reveal that MORs could exist in either pre or post-synaptic sites depending upon the types of neurons and the region of the brain. Therefore, to better understand drug addiction, we will investigate how opioids modulate excitatory synaptic transmissions in different regions of the brain. (2) Learning and using the two-photon microscopic technique to investigate AMPA receptor trafficking during chronic opioid exposure: Chronic treatment of morphine decreases the amplitude of miniature EPSCs, suggesting a removal of post-synaptic AMPA receptors. The objective of this approach is to lay a solid foundation for the next future research plan when my funded R01 grant is up for competitive renewal. This next future research plan is to clarify the cellular mechanism underlying the trafficking of AMPA receptors during opioid exposure. In addition, this K02 award will also allow me to devote extra effort to my training in opioid pharmacology. I will attend seminars and meetings in the Department of Neuroscience and the NIDA funded Basic Center for Molecular and Cellular Biology of Drug Abuse at the University of Minnesota. I will regularly attend the NIDA funded summer courses at Cold Spring Harbor and participate in national and international scientific meetings of neuroscience and pharmacology.